Coordinate Hyperactivation of Notch1 and Ras/MAPK Pathways Correlates with Poor Patient Survival: Novel Therapeutic Strategy for Aggressive Breast Cancers

Aberrant activation of Notch and Ras pathways has been detected in breast cancers. A synergy between these two pathways has also been shown in breast cell transformation in culture. Yet, the clinical relevance of Notch-Ras cooperation in breast cancer progression remains unexplored. In this study, we show that coordinate hyperactivation of Notch1 and Ras/MAPK pathways in breast cancer patient specimens, as assessed by IHC for cleaved Notch1 and pErk1/2, respectively, correlated with early relapse to vital organs and poor overall survival. Interestingly, majority of such Notch1 (high)Erk(high) cases encompassed the highly aggressive triple-negative breast cancers (TNBC), and were enriched in stem cell markers. We further show that combinatorial inhibition of Notch1 and Ras/MAPK pathways, using a novel mAb against Notch1 and a MEK inhibitor, respectively, led to a significant reduction in proliferation and survival of breast cancer cells compared with individual inhibition. Combined inhibition also abrogated sphere-forming potential, and depleted the putative cancer stem-like cell subpopulation. Most importantly, combinatorial inhibition of Notch1 and Ras/MAPK pathways completely blocked tumor growth in a panel of breast cancer xenografts, including the TNBCs. Thus, our study identifies coordinate hyperactivation of Notch1 and Ras/MAPK pathways as novel biomarkers for poor breast cancer outcome. Furthermore, based on our preclinical data, we propose combinatorial targeting of these two pathways as a treatment strategy for highly aggressive breast cancers, particularly the TNBCs that currently lack any targeted therapeutic module. (C) 2014 AACR.

Design of an Automated Dispenser Unit

This paper presents our work on developing an automated micro positioner and a low cost disposable dispenser module having a disposable dispenser core. The dispenser core is made up of Polydimethylsiloxane (PDMS). Once the user specifies the dispensing location in the Graphical User Interface (GUI), the movement of the micropositioner is automatic. The design, fabrication and characterization results of the dispenser module are also presented. The dispensing experiments are performed with Di-Ethanol Amine as the working reagent. The minimum dispensed volume achieved is about 4 nL.

Maze solving automatons for self-healing of open interconnects: Modular add-on for circuit boards

We present the circuit board integration of a self-healing mechanism to repair open faults. The electric field driven mechanism physically restores fractured interconnects in electronic circuits and has the ability to solve mazes. The repair is performed by conductive particles dispersed in an insulating fluid. We demonstrate the integration of the healing module onto printed circuit boards and the ability of maze solving. We model and perform experiments on the influence of the geometry of conductive particles as well as the terminal impedances of the route on the healing efficiency. The typical heal rate is 10 mu m/s with healed route having mean resistance of 8 k Omega across a 200 micron gap and depending on the materials and concentrations used. (C) 2015 AIP Publishing LLC.

A faster algorithm for testing polynomial representability of functions over finite integer rings

Given a function from Z(n) to itself one can determine its polynomial representability by using Kempner function. In this paper we present an alternative characterization of polynomial functions over Z(n) by constructing a generating set for the Z(n)-module of polynomial functions. This characterization results in an algorithm that is faster on average in deciding polynomial representability. We also extend the characterization to functions in several variables. (C) 2015 Elsevier B.V. All rights reserved.

Graphene based multifunctional flame sensor

Recently, graphene has attracted much attention due to its unique electrical and thermal properties along with its high surface area, and hence presents an ideal sensing material. We report a novel configuration of a graphene based flame sensor by exploiting the response of few layer graphene to a flame along two different directions, where flame detection results from a difference in heat transfer mechanisms. A complete sensor module was developed with a signal conditioning circuit that compensates for any drift in the baseline of the sensor, along with a flame detection algorithm implemented in a microcontroller to detect the flame. A pre-defined threshold for either of the sensors is tunable, which can be varied based on the nature of the flame, hence presenting a system that can be used for detection of any kind of flame. This finding also presents a scalable method that opens avenues to modify complicated sensing schemes.

Experimental Study on Switching Characteristics of an Inverter Leg Consisting of IGBTs of Dissimilar Makes

Usually the top and bottom IGBT devices in an inverter leg are of the same make (i.e. from same manufacturer). At low power level, these two devices even may be contained in the same module. However at high power levels the top and bottom devices are in separate modules. Sometimes, in the event of device failure, device of particular make may be replaced by one of another make, but of same ratings (on account of non-availability of the original make). This paper investigates the effect of such intermixing of two different makes of high power IGBTs in an inverter leg on the switching characteristics. The switching transitions between IGBT and diode of similar make and those of IGBT and diode of dissimilar make are compared experimentally at various DC link voltages and currents. The comparisons are made in terms of, IGBT peak turn-on di/dt, IGBT peak turn-off di/dt, peak diode reverse recovery current (I-rr), peak IGBT voltage overshoot and switching energy losses.

Unified Continuum Damage Model for Matrix Cracking in Composite Rotor Blades

This paper deals with modeling of the first damage mode, matrix micro-cracking, in helicopter rotor/wind turbine blades and how this effects the overall cross-sectional stiffness. The helicopter/wind turbine rotor system operates in a highly dynamic and unsteady environment leading to severe vibratory loads present in the system. Repeated exposure to this loading condition can induce damage in the composite rotor blades. These rotor/turbine blades are generally made of fiber-reinforced laminated composites and exhibit various competing modes of damage such as matrix micro-cracking, delamination, and fiber breakage. There is a need to study the behavior of the composite rotor system under various key damage modes in composite materials for developing Structural Health Monitoring (SHM) system. Each blade is modeled as a beam based on geometrically non-linear 3-D elasticity theory. Each blade thus splits into 2-D analyzes of cross-sections and non-linear 1-D analyzes along the beam reference curves. Two different tools are used here for complete 3-D analysis: VABS for 2-D cross-sectional analysis and GEBT for 1-D beam analysis. The physically-based failure models for matrix in compression and tension loading are used in the present work. Matrix cracking is detected using two failure criterion: Matrix Failure in Compression and Matrix Failure in Tension which are based on the recovered field. A strain variable is set which drives the damage variable for matrix cracking and this damage variable is used to estimate the reduced cross-sectional stiffness. The matrix micro-cracking is performed in two different approaches: (i) Element-wise, and (ii) Node-wise. The procedure presented in this paper is implemented in VABS as matrix micro-cracking modeling module. Three examples are presented to investigate the matrix failure model which illustrate the effect of matrix cracking on cross-sectional stiffness by varying the applied cyclic

Router Attack toward NoC-enabled MPSoC and Monitoring Countermeasures against such Threat

The growing number of applications and processing units in modern Multiprocessor Systems-on-Chips (MPSoCs) come along with reduced time to market. Different IP cores can come from different vendors, and their trust levels are also different, but typically they use Network-on-Chip (NoC) as their communication infrastructure. An MPSoC can have multiple Trusted Execution Environments (TEEs). Apart from performance, power, and area research in the field of MPSoC, robust and secure system design is also gaining importance in the research community. To build a secure system, the designer must know beforehand all kinds of attack possibilities for the respective system (MPSoC). In this paper we survey the possible attack scenarios on present-day MPSoCs and investigate a new attack scenario, i.e., router attack targeted toward NoC architecture. We show the validity of this attack by analyzing different present-day NoC architectures and show that they are all vulnerable to this type of attack. By launching a router attack, an attacker can control the whole chip very easily, which makes it a very serious issue. Both routing tables and routing logic-based routers are vulnerable to such attacks. In this paper, we address attacks on routing tables. We propose different monitoring-based countermeasures against routing table-based router attack in an MPSoC having multiple TEEs. Synthesis results show that proposed countermeasures, viz. Runtime-monitor, Restart-monitor, Intermediate manager, and Auditor, occupy areas that are 26.6, 22, 0.2, and 12.2 % of a routing table-based router area. Apart from these, we propose Ejection address checker and Local monitoring module inside a router that cause 3.4 and 10.6 % increase of a router area, respectively. Simulation results are also given, which shows effectiveness of proposed monitoring-based countermeasures.

Experimental characterisation and performance evaluation of a coaxial current transformer for measurement of insulated gate bipolar transistor switching current

Measurement of device current during switching characterisation of an insulated gate bipolar transistor (IGBT) requires a current sensor with low insertion impedance and high bandwidth. This study presents an experimental procedure for evaluating the performance of a coaxial current transformer (CCT), designed for the above purpose. A prototype CCT, which can be mounted directly on a power terminal of a 1200 V/50 A half-bridge IGBT module, is characterised experimentally. The measured characteristics include insertion impedance, gain and phase of the CCT at different frequencies. The bounds of linearity within which the CCT can operate without saturation are determined theoretically, and are also verified experimentally. The experimental study on linearity of the CCT requires a high-amplitude current source. A proportional-resonant (PR) controller-based current-controlled half-bridge inverter is developed for this purpose. A systematic procedure for selection of PR controller parameters is also reported in this study. This set-up is helpful to determine the limit of linearity and also to measure the frequency response of the CCT at realistic amplitudes of current in the low-frequency range.

Divergence in Patterns of Leaf Growth Polarity Is Associated with the Expression Divergence of miR396

Lateral appendages often show allometric growth with a specific growth polarity along the proximo-distal axis. Studies on leaf growth in model plants have identified a basipetal growth direction with the highest growth rate at the proximal end and progressively lower rates toward the distal end. Although the molecular mechanisms governing such a growth pattern have been studied recently, variation in leaf growth polarity and, therefore, its evolutionary origin remain unknown. By surveying 75 eudicot species, here we report that leaf growth polarity is divergent. Leaf growth in the proximo-distal axis is polar, with more growth arising from either the proximal or the distal end; dispersed with no apparent polarity; or bidirectional, with more growth contributed by the central region and less growth at either end. We further demonstrate that the expression gradient of the miR396-GROWTH-REGULATING FACTOR module strongly correlates with the polarity of leaf growth. Altering the endogenous pattern of miR396 expression in transgenic Arabidopsis thaliana leaves only partially modified the spatial pattern of cell expansion, suggesting that the diverse growth polarities might have evolved via concerted changes in multiple gene regulatory networks.

Action of Hopf on the twisted modular Hecke operator

Let Gamma subset of SL2(Z) be a principal congruence subgroup. For each sigma is an element of SL2(Z), we introduce the collection A(sigma)(Gamma) of modular Hecke operators twisted by sigma. Then, A(sigma)(Gamma) is a right A(Gamma)-module, where A(Gamma) is the modular Hecke algebra introduced by Connes and Moscovici. Using the action of a Hopf algebra h(0) on A(sigma)(Gamma), we define reduced Rankin-Cohen brackets on A(sigma)(Gamma). Moreover A(sigma)(Gamma) carries an action of H 1, where H 1 is the Hopf algebra of foliations of codimension 1. Finally, we consider operators between the levels A(sigma)(Gamma), sigma is an element of SL2(Z). We show that the action of these operators can be expressed in terms of a Hopf algebra h(Z).

Timing Calculations for a General N-Level Dodecagonal Space Vector Structure Using Only Reference Phase Voltages

Multilevel inverters with dodecagonal (12-sided polygon) voltage space vector (SV) structures have advantages like extension of linear modulation range, elimination of fifth and seventh harmonics in phase voltages and currents for the full modulation range including extreme 12-step operation, reduced device voltage ratings, lesser dv/dt stresses on devices and motor phase windings resulting in lower EMI/EMC problems, and lower switching frequency-making it more suitable for high-power drive applications. This paper proposes a simple method to obtain pulsewidth modulation (PWM) timings for a dodecagonal voltage SV structure using only sampled reference voltages. In addition to this, a carrier-based method for obtaining the PWM timings for a general N-level dodecagonal structure is proposed in this paper for the first time. The algorithm outputs the triangle information and the PWM timing values which can be set as the compare values for any carrier-based hardware PWM module to obtain SV PWM like switching sequences. The proposed method eliminates the need for angle estimation, computation of modulation indices, and iterative search algorithms that are typical in multilevel dodecagonal SV systems. The proposed PWM scheme was implemented on a five-level dodecagonal SV structure. Exhaustive simulation and experimental results for steady-state and transient conditions are presented to validate the proposed method.

Quaternary cocrystals: combinatorial synthetic strategies based on long-range synthon Aufbau modules (LSAM)

A synthetic strategy is outlined whereby a binary cocrystal may be developed in turn into a ternary and finally into a quaternary cocrystal. The strategy hinges on the concept of the long-range synthon Aufbau module (LSAM) which is a large supramolecular synthon containing more than one type of intermolecular interaction. Modulation of these interactions may be possible with the use of additional molecular components so that higher level cocrystals are produced. We report six quaternary cocrystals here. All are obtained as nearly exclusive crystallization products when four appropriate solid compounds are taken together in solution for crystallization.

Flow Investigation of Linear Cluster Plug Nozzle

Computational and experimental tools have been used to understand the linear cluster plug nozzle flowfield for a range of pressure ratios. The experimental cluster configuration is arrived at from a linear plug nozzle by introducing splitter plates in the primary nozzle, and computational analysis of corresponding geometry is also carried out. The flow development on the plug surface has been analyzed for two different cluster module spacings. The interactions between the cluster module jets is a complex one with a three-dimensional shock structure because of the differential end condition the shock experiences on the plug wall and freejet boundary. A prominent streamwise vorticity resulting from curvature of the shock is also seen along the length of the plug downstream of the module junctions. The out-of-phase wave interactions occurring along the module centerline and the splitter plate centerline, resulting in a wavy surface-limiting streamline pattern, particularly at lower pressure ratios, is explained.

Reduced common-mode voltage operation of a new seven-level hybrid multilevel inverter topology with a single DC voltage source

In this study, analysis of extending the linear modulation range of a zero common-mode voltage (CMV) operated n-level inverter by allowing reduced CMV switching is presented. A new hybrid seven-level inverter topology with a single DC supply is also presented in this study and inverter operation for zero and reduced CMV is analysed. Each phase of the inverter is realised by cascading two three-level flying capacitor inverters with a half-bridge module in between. Proposed inverter topology is operated with zero CMV for modulation index <86% and is operated with a CMV magnitude of V-dc/18 to extend the modulation range up to 96%. Experimental results are presented for zero CMV operation and for reduced common voltage operation to extend the linear modulation range. A capacitor voltage balancing algorithm is designed utilising the pole voltage redundancies of the inverter, which works for every sampling instant to correct the capacitor voltage irrespective of load power factor and modulation index. The capacitor voltage balancing algorithm is tested for different modulation indices and for various transient conditions, to validate the proposed topology.